Notch signaling plays crucial roles in many developmental pathways, with Notch mutations linked to several developmental disorders. Because many pediatric malignancies arise from dysregulated development, roles for Notch signaling in these cancers are to be expected. Evidence to support this is now emerging as the Notch pathway is being explored in more pediatric cancers. Not surprisingly, Notch appears to play diverse roles in different malignancies, effecting differentiation, metastasis, cancer "stem cells," and angiogenesis. As examples, although activating mutations of Notch1 are found in the majority of T-cell acute lymphoblastic leukemia (ALL) cases, Notch/HES1 signaling appears to play a tumor suppressor role in precursor B-cell ALL; although Notch/HES1 signaling appears to contribute to osteosarcoma metastasis, Notch signaling also promotes medulloblastoma "stem cell" survival and contributes to angiogenesis in neuroblastoma. Further understanding of the roles of Notch signaling in specific pediatric cancers will provide a rationale for Notch-based therapeutic strategies.